NM_182914.3:c.20448C>T

Variant names:

• chr14-64224526-C-T
• rs546213944
• NM_182914.3:c.20448C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_182914.3(SYNE2):​c.20448C>T​(p.Ser6816Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.60
• Publications: 1 publications found

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ESR2 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ovarian dysgenesis 8

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-64224526-C-T is Benign according to our data. Variant chr14-64224526-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 538367.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000164 (25/152244) while in subpopulation AMR AF = 0.000196 (3/15290). AF 95% confidence interval is 0.0000528. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.20448C>T	p.Ser6816Ser	synonymous	Exon 114 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.20379C>T	p.Ser6793Ser	synonymous	Exon 113 of 115	NP_055995.4
	SYNE2	NM_182913.4		c.1392C>T	p.Ser464Ser	synonymous	Exon 9 of 11	NP_878917.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.20448C>T	p.Ser6816Ser	synonymous	Exon 114 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.20379C>T	p.Ser6793Ser	synonymous	Exon 113 of 115	ENSP00000341781.4
	SYNE2	ENST00000458046.6	TSL:1	c.1392C>T	p.Ser464Ser	synonymous	Exon 9 of 11	ENSP00000391937.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152126 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251456 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152244 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.000196

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:1

Jan 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.72
PhyloP100		-1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs546213944; hg19: chr14-64691244;